JPH08799B2 - Relaxing β-adrenergic blocker - Google Patents

Description

Description: FIELD OF THE INVENTION The present invention is a soft β-adrenergic blocker (or anti-adrenergic drug) useful in the treatment or prevention of cardiovascular disease as well as the treatment of glaucoma, at least. Provided are novel compounds containing one aromatic nucleus.

BACKGROUND OF THE INVENTION Many β-adrenergic blockers are known and in use. Unfortunately, however, they are generally susceptible to oxidative metabolic degradation. Many of the metabolites of these drugs also have a prominent β-blocking effect, but due to their different pharmacokinetic properties, it is difficult to ensure drug administration and maximum therapeutic effect. For example, the bufuralol metabolite exhibits a longer biological half-life than the original drug (bufuralol). Francis et al., Biomedical Mass Spectrometry (Biomed.Mass Spectrometry), 3, 281
-285 (1976). Therefore, there is a known β especially for patients with angina, hypertension or sudden arrhythmias during surgery.
When administering a blocker for therapeutic purposes, it is difficult to determine the required dosage. From this point of view, it is particularly important to design β-blockers that can be metabolized in one step to an inactive metabolite in a simple, predictable and controllable manner, regardless of the patient's condition and other drugs used in combination. Would be desirable. However, this would need to avoid oxidative metabolism.

The present invention has already proposed a general solution of palliative drugs for such purpose. One specific means is the inactive metabolite method. Bodor, Second Guide to Drug Research
Minutes of the IUPAC-IUPHAR Symposium, Noordwijkerhou
t, JAKeverling Buisman (ed.), Elsevier Scientific
Published by Publishing Co. (Amsterdam), (1982); Bod
or, Belgian Patent No. 889,563 (November 03, 1981); Chemical Abstracts (Chem.Abstr.), 97: 6651n (19
82). The principle of this inactive metabolite method is as follows: (1) This design method starts with known inactive metabolites of the drug.

(2) This metabolite is denatured to obtain a structure (isosteric and / or isoelectronic) similar to the starting drug or its analogues.

(3) Design the structure and metabolism of this novel mitigating compound to generate the starting inactive metabolite in one step without passing through toxic intermediates.

(4) Modulation of transport and binding properties as well as metabolism and pharmacokinetic rates by molecular manipulations at the activation stage.

However, it is not necessary to have isolation of inactive metabolites. It is also possible to design inactive metabolites in the course of the general drug design method described above, based on knowledge of activity and structural requirements for excretion and enzymatic cleavage.

Recently, American Hospital Supply Corporation International Application Number PCT / US81 / 01514 (International Publication Number
WO82 / 01869 published on Jun. 10, 1982) describes a series of short-acting β-adrenergic blocking compounds containing an ester moiety, which are structurally part of the compound of the present invention. Related to. However, this PCT application addresses the problem addressed by the present invention, namely, how to avoid β-blockers that are metabolized to inactive metabolites in a single step that is simple, predictable and controllable while avoiding oxidative metabolism. It doesn't seem to deal with the issue of designing. Furthermore, the esters of this PCT application are generally less complex than those of the invention described below. Erhardt et al, Journal of Medical Chemistry (J.Med.Ch
em.), 25 , 1408-1412 (1982). Similar simple alkyl esters have long been described in the literature. For example, Barrett et al US Pat. No. 3,663,607 (issued May 16, 1972). See also JP-A-57-230664 (published December 27, 1982).

SUMMARY OF THE INVENTION AND OBJECTS: From the above description, it is an object of the present invention to provide a novel class of β-adrenergic drugs that are metabolized to inactive metabolites in one step in a simple, predictable and controllable manner. . Another object of the present invention is to provide a novel β-adrenergic drug that does not undergo significant oxidative metabolism. Another object of the present invention is to apply the above-mentioned general-purpose inactive metabolite method proposed by the present inventor to the design of novel relaxed β-blockers.

The above and other objects of the present invention are achieved by providing a compound represented by the following general formula: In the above formula, n be an integer from 0 to (including 0 and 10); R is, C ₆ -C ₁₈ polycycloalkyl -C _p H _2p - group (provided that
p is 0, 1, 2 or _{3); - CH 2 -X-} R 2 group (wherein,
X represents S, SO or SO ₂ , and R ₂ represents a C _{1 to} C ₇ alkyl group); (However, R ₅ represents hydrogen or a C _{1 to} C ₇ alkyl group,
R ₆ represents a C ₁ -C ₇ alkyl group); or (However, R ₅ has the same meaning as described above, R ₇ and R ₈ may be the same or different and each represents hydrogen or a C ₁ -C ₇ alkyl group); R ₁ is C ₁ -C ₇ alkyl Means a group; and Ar is an unsubstituted phenylene group or C ₁ -C ₇ alkyl, C ₁
-C ₇ alkyl -O-C ₁ -C ₇ alkylene -, C ₂ ~C ₈ alkenyl, C ₁ ~ ₇ alkyl -S-, C ₂ ~C ₈ alkenyl -O
-, C ₃ ~C ₁₂ cycloalkyl, C ₁ -C ₇ alkyl -CONH
A phenylene group substituted with a —, C ₁ -C ₇ alkyl-CO—, or H ₂ NCO—C ₁ -C ₇ alkylene- group.

The compounds of the invention do not suffer from the active metabolites exhibited by many known β-blockers. General formula (I)
When administered to a mammal, it undergoes an enzymatic hydrolysis (ie, esterase) metabolic process much faster than oxidative metabolism, resulting in a hydrolyzed metabolite with little or no β-adrenergic activity. Reasonably designed to be. For example, in the case of a group of metoprolol derivatives that is a preferred embodiment of the present invention, this is a phenylacetic acid derivative when it is inactivated by hydrolysis.
That is, it is designed to give a compound of the following structural formula.

This compound is one of the inactive metabolites of metoprolol
It is the main metabolite present in urine.
[For example, Borg et al, Actor Pharmacology
And Toxicology (Acta Pharmacol.Toxicol., 3
6 , (Additional V), 125-135 (1975). The rate of hydrolytic inactivation can be controlled by the structure of the above ester.

Therefore, the compounds of the present invention show an excellent β-blocking effect without causing side effects for a certain duration depending only on the rate of hydrolysis and metabolism. As a result, the compounds of the invention facilitate the control and retention of sufficient therapeutic effect at the desired onset time. The onset time is usually shorter compared to conventional β-adrenergic blockers. As such, the compounds of the invention are expected to be particularly useful in the treatment of arrhythmias, ischemic heart disease and hypertension that may occur with surgery. The compounds of the invention are also expected to be particularly useful when used in the treatment of glaucoma, not only because of the topical administration of the compounds of the invention to the eye that reduces intraocular pressure, but also in their "alleviation." Because it is inactivated during absorption due to its "sexual" nature, it avoids the typical systemic side effects of β-blockers that accompany the actions of known β-blockers for the treatment of glaucoma. Depends on

Detailed Description of the Invention: With respect to the various groups embraced by the general terms used herein, the following definitions and explanations may apply: The divalent group represented by Ar is as follows: phenylene, Ie the formula: And especially 1,4-phenylene and 1,3-phenylene groups, which are optionally C ₁ -C ₇ alkyl groups (eg CH ₃ C
H ₂ - or _{CH 3 -); C 1 ~C} 7 alkyl -O-C ₁ ~C ₇ alkylene - group _{(eg, CH 3 OCH 2 CH 2 -} ); C 2 ~C 8 alkenyl group (e.g., CH _{2 = CH-CH 2 -);} C 1 ~C 7 alkyl -S- group _{(eg, CH 3 -S -); C} 2 ~C 8 alkenyl -O- group (e.g., CH
_{2 = CH-CH 2 -O -} ); C 3 ~C 12 cycloalkyl group (e.g., cyclopentyl); C ₁ ~C ₇ alkyl -CONH- group (e.g., CH ₃ CH
₂ CH ₂ CONH- or CH ₃ CONH-); C ₁ -C ₇ alkyl-CO-
A group (eg, CH ₃ CO—); and / or one or more substituents such as H ₂ NCO—C ₁ -C ₇ alkylene-group (eg, H ₂ NCO—CH ₂ —) The divalent group represented by Ar is preferably a divalent group represented by the general formula (I) The group has a structure in which a hydrogen atom in a corresponding ring of a known β-blocker is simply substituted, or a ring substituent which is not essential for the action of the corresponding known β-blocker, such as a lower alkyl group, a lower alkyl-O-lower It is selected to have an alkylene-group, lower alkyl-CONH-group or H ₂ NCO-lower alkylene-substituted substitution substituted structure. Particularly preferred compounds of the invention have the above structural relationships to metoprolol, alprenolol, tiprenolol, oxyprenolol, penbutolol, acebutolol, atenolol or plactrol.

The alkyl, alkenyl and alkylene groups included in the various structural factors in the general formula (I) may be linear or branched groups containing the indicated number of carbon atoms. The term "lower" as used with respect to such groups means that it may contain up to 7 carbon atoms.

Specific examples of the alkyl group (the R ₁ group itself or the alkyl group contained as a part of the R group or the Ar group) included in the general formula (I) include methyl, ethyl, propyl, butyl and pentyl. , Hexyl and heptyl groups, and their branched chain isomers, such as isopropyl,
Examples include isobutyl and tert-butyl groups. Preferred R ₁ groups are isopropyl and tert-butyl groups.

Examples of alkenyl groups included as part of the various R and Ar groups include vinyl, propenyl and butenyl, and branched chain groups having 3 or more carbon atoms.

Examples of the alkylene moiety included in C _n H _2n (where n is not zero) and the alkylene moiety included as a moiety in various specific examples of the R and Ar groups include methylene, ethylene, trimethylene, and 2 -Methyltrimethylene, 2,2
-Dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene and the like.

Alkoxy, alkylthio, alkylsulfinyl,
Alkylsulfonyl, alkoxycarbonyl, alkanoyloxy, monoalkylamino, dialkylamino,
The monoalkylcarbamoyl and dialkylcarbamoyl groups are of the following types, respectively.

-O- alkyl -S- alkyl -SO- alkyl -SO ₂ - alkyl -NH-alkyl and (In the above formula, the alkyl groups are as defined and exemplified above).

Polycycloalkyl -C represented by R _p H _2p - group,
Consists of 2 or more rings, optionally having 1 or 2 or more alkyl substituents, and having a total number of carbon atoms in the ring portion of 6 to
18 is a saturated alicyclic hydrocarbon system in which rings are linked by a bridge. Corresponding alicyclic hydrocarbon bridging bound unsaturated "C ₆ -C ₁₈ polycycloalkenyl -C _p H _2p -
The term "base" is used. Examples of such polycycloalkyl and polycycloalkenyl groups include adamantyl (especially 1- or 2-adamantyl), adamantylmethyl (especially 1-adamantylmethyl), adamantylethyl (especially 1-adamantylethyl), bornyl, norbornyl (eg. , Exo-norbornyl or end
o-norbornyl), norbornenyl (eg 5-norbornen-2-yl), norbornylmethyl (eg 2-norbornylmethyl) and norbornylethyl (eg 2
-Norbornylethyl). Thus, for polycyclic groups, p is preferably 0, 1 or 2.

The compound of general formula (I) has the general formula (In the formula, R, n and Ar have the same meanings as above, and Z is (Wherein Hal is a halogen atom, especially Cl or Br) and is represented by the general formula NH ₂ R ₁ (III), in which R ₁ has the same meaning as above. It can be produced by reacting with a primary amine. This method
It is preferable to carry out in the presence of an inert solvent, but it can also be carried out in the absence of a solvent. Although the time and temperature are not particularly limited, this reaction is generally performed at a temperature of about room temperature to about 200 ° C. (preferably about 60 to 120 ° C.) for about 30 minutes to 24 hours. Suitable inert solvents include ethers such as dioxane, tetrahydrofuran and ethylene glycol monomethyl ether; aromatic hydrocarbons such as benzene, toluene or xylene; lower alcohols such as methanol, ethanol and isopropanol; and ethyl acetate, dimethyl. Esters such as formamide and dimethyl sulfoxide are included. The above reaction method is often carried out in the presence of a basic compound. Examples of such basic compounds are inorganic bases such as sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium amide or sodium hydride; or triethylamine, tripropylamine, pyridine, quinoline, DBN (1,5-diazabicyclo [4.3 .0] non-5
Ene), DBU (1,8-diazabicyclo [5.4.0] undec-7-ene) or Dabco (1,4-diazabicyclo [2.
2.2] Octane) or organic bases such as triethylenediamine. The ratio of the amounts of the two types of reactants used can be selected within a wide range. However, in general, the general formula (II
It is desirable to use the amines of I) in equimolar or excess amounts, preferably equimolar amounts or amounts up to about 7 times in molar ratio.

The starting material of the general formula (II) is the general formula (Wherein R, n and Ar have the same meanings as described above), the corresponding compound represented by the general formula It is conveniently prepared by reacting with an epihalohydrin represented by the formula (wherein Hal means a halogen atom, especially Cl or Br). This method employs suitable basic compounds such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, sodium hydride, metal with or without solvent. Inorganic bases such as sodium, metallic potassium or sodium amide, or piperidine, pyridine, triethylamine, DBN, D
It can be carried out in the presence of an organic base such as BU or Dabco. Suitable solvents are, for example, lower alcohols such as methanol, ethanol or isopropanol; ketones such as acetone; ethers such as dioxane, tetrahydrofuran or ethylene glycol monomethyl ether; or aromatic hydrocarbons such as benzene, toluene or xylene. Is. In this reaction, the epihalohydrin of general formula (V) can be used in an equimolar or excess amount, preferably in a molar amount of about 5 to 15 times, relative to the starting material of general formula (IV). The process can be carried out at temperatures of about 0-150 ° C, preferably about 50-100 ° C. Usually, the reaction product is a mixture of corresponding compounds of the (2,3-epoxy) propoxy type and the 3-halogeno-2-hydroxypropoxy type, both of which are contained in the general formula (II), and the reaction product is It can be used as such for the preparation of compounds of formula (I).

The starting materials of the general formula (IV), (wherein, n and Ar are the same meaning) general formula _{HOOC-C n H 2n -Ar-} OH (VI) acids or the corresponding acid chloride represented by or The acid anhydride can be produced by esterification by reaction with an alcohol represented by the general formula ROH (VII) (wherein R has the same meaning as described above).
The reaction conditions, solvent, etc. will differ depending on the type of reactant used. Generally, when the acid of general formula (VI) is used as a starting material, the process is carried out in the presence of a conventional esterification catalyst. Examples of the esterification catalyst are hydrogen chloride gas, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, inorganic acids such as boron trifluoride or hypochlorous acid, or trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, p -Toluenesulfonic acid, benzenesulfonic acid,
There are organic acids such as ethanesulfonic acid, trifluoromethanesulfonic anhydride, thionyl chloride, and acetone dimethyl acetal. Cation exchange resins can also be used as catalysts. The esterification reaction is carried out in the presence or absence of a solvent at about -20 ° C to 200 ° C, preferably about 0 to 150 ° C.
It can be carried out at a temperature of ° C for about 10 minutes to about 20 hours. When a solvent is used, an inert solvent such as aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane or carbon tetrachloride; or diethyl ether, tetrahydrofuran, dioxane or ethylene. Ethers such as glycol monomethyl ether are preferred. General formula ROH alcohol general formula (V
The proportion of the compound I) used is not particularly limited and can be appropriately selected from a wide range. When a solvent is not used, it is usually desirable to use the above alcohol in excess, but when a solvent is used, the alcohol is represented by the general formula (V
It is desirable to use an equimolar amount to 5 times, and more preferably an equimolar amount to 2 times the molar amount of the compound of I). This reaction can be advantageously carried out using a desiccant (dehydrating agent) such as anhydrous calcium chloride, anhydrous cupric sulfate, anhydrous calcium sulfate and phosphorus pentoxide.

Or the general formula acid ^{(VI), M + - OOC} -C n H 2n -Ar-OH (VIII) ( wherein, n and Ar are as defined above, M ⁺ is Na ⁺
Of the general formula R-Hal (IX), wherein R is as defined above and Hal is a halogen atom, preferably It can also be reacted with a halide of the formula (meaning Cl or Br) to give the corresponding starting material of the general formula (IV).

Sulfinyl group (SO) or sulfonyl group (SO ₂ )
Compounds of the present invention containing a can be prepared by oxidation of the corresponding sulfur-containing compound of the present invention. For example, treatment of a compound of general formula (I) wherein R is —CH ₂ —X—R ₂ and X is S with 1 equivalent of m-chloroperbenzoic acid can give the corresponding sulfinyl derivative. ,
Alternatively, the thio compound can be treated with 2 equivalents of m-chloroperbenzoic acid to form the corresponding sulfonyl derivative. Thus, compounds of general formula (I) in which R contains a sulfur atom, for example R is --CH ₂ --X--R ₂ or Wherein X is S and R ₂ , R ₃ and R ₄ have the same meanings as above, and not only are they useful as relaxed β-adrenergic blockers, but X is SO or SO ₂ . It is also useful as a chemical intermediate for the production of the corresponding palliative drug.

The compounds of the present invention also have the general formula (Wherein n, Ar and R ₁ have the same meanings as described above), and can also be produced by esterifying the corresponding acid under the same conditions as the esterification of the compound of the general formula (VI). .

Equivalent for the purposes of this invention to the compounds of general formula (I) are the corresponding acid addition salts formed with pharmaceutically acceptable acids. Examples of such acids include hydrochloric acid, sulfuric acid, inorganic acids such as hydrobromic acid, and acetic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, malonic acid, methanesulfonic acid, Organic acids such as benzoic acid.

The compound produced by the method detailed above can be isolated by a conventional separation means (eg, solvent extraction, dilution, recrystallization, column chromatography or thin layer chromatography for production).
Can be easily isolated and purified by.

The compounds of the present invention also include their optical isomers.

For use in therapy, for example in the treatment of angina and arrhythmia, a compound of general formula (I) or a salt thereof, containing a compound of general formula (I) or a salt thereof and a pharmaceutically acceptable carrier therefor. Conveniently it is administered in the form of a pharmaceutical composition. Suitable carriers will depend on the desired dosage form of the pharmaceutical composition, but examples of carriers include diluents or excipients such as bulking agents, binders, wetting agents, disintegrating agents, surfactants, lubricants and the like. It

The compounds of the invention or salts thereof may be formulated with a carrier in any desired unit dosage form. Typical unit dosage forms include
There are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, etc., but solutions and suspensions for injection are particularly preferable.

In the manufacture of tablets, carriers widely used in this field can be used, and examples of the carriers include lactose, sucrose, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin. , Excipients such as crystalline cellulose and silicic acid; binders such as water, ethanol, propanol, simple syrup, glucose, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, calcium phosphate and polyvinylpyrrolidone; dry starch, arginine Sodium acid, agar powder, kelp (laminaria) powder, sodium bicarbonate, calcium carbonate, Tweens,
Disintegrators such as sodium lauryl sulfate, stearic acid monoglyceride, starch and lactose; Disintegration inhibitors such as sucrose, stearin, cocoa butter and hydrogenated oils; Absorption enhancers such as quaternary ammonium base and sodium lauryl sulfate; glycerin and Wetting agents such as starch; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; as well as refined talc, stearates, boric acid powder, Macrogol
And lubricants such as solid polyethylene glycol.

In the production of pills, known carriers widely used in this field can also be used, and examples of the carrier include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin and talc. Binders such as powdered gum arabic, powdered tragacanth, gelatin and ethanol; and disintegrating agents such as kelp and agar. In the case of tablets, sugar-coated tablets, gelatin film-coated tablets, enteric-coated tablets, film-coated tablets, and double-layered or multi-layered coated tablets may be produced by further coating with conventional coating materials.

Also in the case of forming suppositories, known carriers widely used in this field can be used, and examples of the carriers include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin and semisynthetic glycerides. .

To prepare a pharmaceutical preparation suitable for injection, the solution or suspension is sterilized and preferably made isotonic with blood. Also in the case of producing injectable formulations, carriers commonly used in this field, for example, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, propoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters,
Can be used. In this case, the required amount of sodium chloride, glucose or glycerin may be added to make the preparation isotonic.

In addition, conventional solubilizers, buffers, analgesics and preservatives, as well as colorants, flavors, seasonings, sweeteners and other agents may be added to the pharmaceutical composition as needed or desired.

The amount of the compound of general formula (I) or an acid addition salt thereof to be present in a pharmaceutical composition such as a pharmaceutical composition for treating angina and arrhythmia can be appropriately selected from a wide range, but usually the composition 1 to 70% by weight of the whole is preferable.

The route of administration (eg, for angina) will also depend on the type of pharmaceutical composition used. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules can be administered orally. The injectable preparation can be administered intravenously alone or in combination with an infusion solution such as a glucose solution and an amino acid solution. Injectable formulations may be administered intramuscularly, intradermally,
It can also be administered separately by the subcutaneous or intraperitoneal route.

The dose of the compound of the present invention is selected depending on the usage, purpose of use, and condition of symptoms. For example, when a compound of the invention is administered to a patient for the treatment of angina, hypertension, or sudden arrhythmias during surgery, typically 0.5-6.0 mg.
/ kg of the compound of general formula (I) or an acid addition salt thereof may be administered.

The compounds of the present invention may also be administered continuously at appropriate intervals, such as 30 minutes to 60 minutes.

The compounds of the present invention and their salts reduce intraocular pressure when administered topically / topically to the eye, and thus are used in the treatment of glaucoma patients or in other patients in need of reduced intraocular pressure (e.g., ocular). It is particularly useful for treating patients with high internal pressure and at risk of developing glaucoma. The compound of the present invention and a salt thereof are prepared by formulating an intraocular pressure-reducing effective amount of the selected β-blocker of the present invention together with a nontoxic carrier acceptable for the ophthalmic drug for such purpose. It can be conveniently administered. Suitable carriers will be apparent to those skilled in the field of ophthalmic formulation. Of course, the choice of a suitable carrier is dependent upon the type of dosage form desired (eg, the β-blocker dosage form is an ophthalmic solution or suspension (typically for use as an eye drop), an eye). Ointments or creams, or ophthalmic gels]. The preferred dosage form is a solution, which contains water in addition to the active ingredient, with water predominantly. Minor amounts of other ingredients, such as pH adjusting agents (eg, bases such as NaOH), emulsifying or dispersing agents, buffers, preservatives, wetting agents and gelling agents (eg, methylcellulose) can also be present. Particularly preferably, the ophthalmic composition is a sterile isotonic buffered aqueous solution. In general, ophthalmic compositions containing the β-blocker of the present invention are already described in patent or non-patent literature as being suitable for ophthalmic compositions containing known β-blockers such as timolol and labetrol. It can be produced by a conventional method and may contain various inactive ingredients or carriers described in such documents. The amount of β-blocker of the present invention present in the ophthalmic composition will, of course, vary with the type of β-blocker used and the type of dosage form chosen. Generally, the ophthalmic composition has the general formula (I)
Of the compound of 0.01 to 5%, preferably 0.25 to 2.5%. In other words, 0.1-50 mg per ml of solution,
It will preferably contain from 2.5 to 25 mg of the compound of the invention (free base). The dosage when administered ophthalmically is determined depending on the kind of the compound used and the body weight and condition of the patient, but in any case, it is an amount sufficient to cause a significant decrease in intraocular pressure.

To further illustrate the present invention and its advantages, specific examples of compounds of general formula (I) are given below. However, it will be understood that these specific examples are provided by way of illustration only and are not intended to be limiting in any way. The preparation of the starting materials used is also illustrated in the examples below. In the following examples, all melting points or melting temperatures are uncorrected values, and are values obtained by using an electrothermal capillary melting point measuring device.

Example 1 4-hydroxyphenylacetic acid (7.6 g, 0.05 mol) in ethanol (100 ml) was added with potassium hydroxide (2.8 g, 0.0
(5 mol) was added with stirring and ice cooling. The melting point of the white crystalline potassium salt separated by filtration is about 275-277.
C, which was obtained in a yield of 90.5%.

The resulting potassium salt of 4-hydroxyphenylacetic acid (9.5 g, 0.05 mol) was suspended in dimethylformamide (25 ml). Chloromethyl pivalate (7.53 g, 0.05 mol) was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into ice water and ethyl acetate (100 ml)
It was extracted with. The ethyl acetate layer was washed first with 5% aqueous NaHCO ₃ solution (100 ml) and then twice with water, then dried over anhydrous MgSO ₄ , filtered and evaporated to remove pivalyloxymethyl.
4-Hydroxyphenylacetate, mp 159-161 ° C was obtained (70.2% yield).

Example 2 Pivalyloxymethyl-4-hydroxyphenylacetate (7.0 g, 0.05 mol) was dissolved in acetone (50 ml) and epichlorohydrin (40 ml) was added. The mixture was refluxed in the presence of DBU (1 ml, 0.007 mol) for 2 hours and then left to stir at room temperature for the best time. The resulting reaction mixture was evaporated in vacuum. The epoxide residue was added to acetonitrile (80m
l) dissolved in isopropylamine (20 ml, 0.23 mol)
Was added, the reaction mixture was stirred at room temperature overnight, refluxed for 4 hours and then evaporated. The resulting free amine base was purified by acid and base extraction from ether. After evaporating the ether, the remaining extract was extracted with ethyl ether.
Partition with an aqueous solution of 1M KOH and treat the ether layer with 1M HCl.
After washing with water and basifying the acidic layer with 1M aqueous KOH, fresh anhydrous ethyl ether was added to it. The ether layer was separated, dried over anhydrous MgSO _4, and filtered. Equivalent amount of oxalic acid was dissolved in acetone and added dropwise. The precipitated oxalate salt was filtered off and dried. It had a melting point of 123-124 ° C. Pivalyloxymethyl-4-, a molten base
(2-Hydroxy-3-isopropylamino) propoxyphenylacetate has the structure:

The identity of this product was confirmed by NMR and elemental analysis.

Example 3 1-Adamantane ethanol (10 g, 0.05 mol), 4
-Hydroxyphenylacetic acid (8.43 g, 0.05 mol) and p-toluenesulfonic acid (1 g, 0.006 mol) were refluxed in benzene (100 ml) for 8 hours while continuously separating water, and then left to stir overnight. The residue was washed first with 5% aqueous sodium hydrogen carbonate solution (50 ml) then twice with water (50 ml), then dried over anhydrous MgSO ₄ and filtered. The filtrate was concentrated in vacuo to give (adamanto-1-yl) ethyl-4-hydroxyphenylacetate.

(Adamant-1-yl) ethyl-4-hydroxyphenylacetate was dissolved in epichlorohydrin (50 ml) and refluxed in the presence of DBU (1 ml, 0.007 mol) for 2 hours. The residue was dissolved in acetonitrile (100 ml) and refluxed with isopropylamine (20 ml, 0.23 mol) for 4 hours. The reaction mixture was evaporated in vacuo, and partitioned processing with the residue partitioned between ethyl ether (100ml) and 0.5 N NaHCO ₃ solution (100ml). Separate the ether layer and add 1N HCl (30 ml) to it.
Was added. The aqueous layer was separated, 1M aqueous KOH solution (30 ml) was added and the solution was extracted with ether (100 ml). The aqueous layer was discarded, and the ether layer dried over anhydrous MgSO _4, filtered, and evaporated in vacuo. The oily product obtained was dissolved in acetone (25 ml) and an equivalent amount of oxalic acid was dissolved in acetone (25 ml) and added dropwise with stirring. Acetone was evaporated in vacuo and the residue was partitioned between ether (100ml) and 1M aq KOH (100ml). The ether layer was separated, dried over anhydrous MgSO ₄ ,
Filtered and concentrated in vacuo. The oily residue obtained was dissolved in acetone (25 ml) and an equivalent amount of oxalic acid was added to acetone (25 ml).
And was added dropwise with stirring. The precipitated product was filtered off, dried and recrystallized from acetone. The melting point of the oxalate salt of (adamanto-1-yl) ethyl 4- (2-hydroxy-3-isopropylamino) propoxyphenyl acetate thus obtained was 95-97 ° C. Yield 7
0.9%. The structure of the free base is as follows: The results of NMR and elemental analysis were consistent with the above structure.

Example 4 1-Adamantanemethanol (8.31 g, 0.05 mol),
4-Hydroxyphenylacetic acid (7.6 g, 0.05 mol) and p-toluenesulfonic acid (1 g, 0.006 mol) were refluxed in benzene (100 ml) for 8 hours with continuous water separation. The reaction mixture was allowed to cool with stirring overnight, and then washed with water (100 ml), 5% NaHCO ₃ aqueous solution (100 ml), and then water (100 ml) twice. After drying over anhydrous MgSO ₄ , filtration and concentration in vacuo gave (adamant-1
-Yl) methyl-4-hydroxyphenylacetate was obtained. This product was then converted to piclohydrin (50m
l) and refluxed for 2 hours in the presence of DBU (1 ml, 0.007 mol). Excess epichlorohydrin was removed in vacuo.
The oily residue was dissolved in acetonitrile (100 ml) and mixed with isopropylamine (20 ml, 0.23 mol). The resulting reaction mixture was refluxed for 4 hours. The resulting brown oily residue was partitioned between ethyl ether (100ml) and 1M aqueous KOH (100ml). Separate the ether layer and add 1N H
Cl (30 ml) was added. The obtained hydrochloric acid layer was separated, and ethyl ether (100 ml) and 1M KOH aqueous solution (30 ml) were added to this. The resulting ether layer was separated, dried over anhydrous MgSO ₄ , filtered and evaporated in vacuo to give the crude product of the desired free amine base. This crude product (5.16 g, yield 7
2.5%) is dissolved in acetone (25 ml) and acetone (25 m
Oxalic acid dissolved in l) (1.8 g) was added dropwise with stirring.
The resulting mixture was stirred for 24 hours while adding acetone. The acetone solution was evaporated and the oily residue was partitioned between ether (100 ml) and 1M aqueous KOH solution (100 ml). The ether solution was dried over anhydrous MgSO _4, filtered, and concentrated. The oily residue was dissolved in acetone and an equivalent amount of an oxalic acid solution in acetone was added dropwise. Precipitated (adamant-1-
The oxalate salt of (yl) methyl-4- (2-hydroxy-3-isopropylamino) propoxyphenylacetate was isolated and dried. Its melting point was 55-57 ° C. NM
The R and elemental analysis results were consistent with the structure. The structural formula of the free base is as follows.

Example 5 2-Norboranemethanol (6.34 g, 0.05 mol), 4
-Hydroxyphenylacetic acid (7.6 g, 0.05 mol), p-toluenesulfonic acid (2 g, 0.006 mol) and benzene (1
(00 ml) was refluxed for 8 hours while continuously separating water. Then the solvent was evaporated and the residue was washed with ethyl acetate (100 m
l) and dissolved in 5% NaHCO ₃ aqueous solution (100 ml), and then water (200 ml) twice. After drying over anhydrous MgSO ₄ , filtration and evaporation left an oily residue which was
The desired (norborn-2-yl) methyl-4 by NMR
-Hydroxyphenylacetate was identified.
This product was then dissolved in acetone (50 ml), epichlorohydrin (40 ml) was added and the reaction mixture was combined with DBU (2 ml,
Reflux for 2 hours in the presence of (0.007 mol). Then the reaction mixture was evaporated in vacuo and the oily residue was converted to acetonitoyl (100 m
dissolved in l). Isopropylamine (20 ml, 0.23 mol) was added and the resulting reaction mixture was refluxed for 4 hours, then evaporated to give the desired free amine base as an oil. This oil was dissolved in acetone (50 ml) and an equivalent amount of oxalic acid dissolved in acetone (25 ml) was added dropwise with stirring. The precipitated white crystalline by-product having a melting point of 198 to 200 ° C. was removed. The acetone was evaporated in vacuo and the resulting oily residue was combined with ethyl ether (100 ml) and 1M KOH aqueous solution (100 m).
It was distributed to and from l). The ether layer was separated and to this was added 1M HCl (50 ml). The acidic layer was separated, neutralized with 1M aqueous KOH solution (50 ml) and washed with ethyl ether (10 ml).
0 ml). The ether layer was separated, dried over anhydrous MgSO ₄ , filtered and evaporated to give the desired free amine base as an oil. Water (25 ml) was added to this oil,
Oxalic acid (5.4 g, 0.01 mol) was dissolved in acetone (25 ml) and added dropwise with constant stirring. After cooling, the oxalate salt of (norborn-2-yl) methyl-4- (2-hydroxy-3-isopropylamino) propoxyphenylacetate, which was precipitated, was washed with acetone (200 ml) and washed with a mixed solvent of ethyl acetate and acetone. It was crystallized. Its melting point was 68-70 ° C. The structure of the corresponding free base is:

The results of elemental analysis and NMR were consistent with the above structure.

Example 6 Potassium salt of 4-hydroxyphenylacetic acid (9.5 g, 0.
1 mol) was dissolved in a mixture of dimethyl sulfoxide (80 ml) and hexamethylphosphoramide (5.37 g, 0.1 mol). 2-Chloroacetamide (13.5 g, 0.3 mol) was added and the reaction mixture was first stirred at room temperature for 24 hours and then 1
Heated for hours. The reaction mixture was then evaporated and then cooled. The precipitated product was dissolved in ethyl acetate (150 ml),
Stir, filter and evaporate. The oily residue was converted into ethyl acetate (10
Partitioned between 0 ml) and water (100 ml). The organic layer was separated, dried over anhydrous MgSO ₄ , filtered and evaporated to give the desired ester carbamoylmethyl-4-hydroxyphenylacetate (mp 85-87 ° C) in 48.8% yield.

Carbamoylmethyl-4-hydroxyphenylacetate (10.4 g, 0.01 mol) was dissolved in acetone. Epichlorohydrin (40 ml) was added and the reaction mixture was mixed with DBU (2 m
(l, 0.014 mol) for 2 hours. The resulting mixture was then evaporated to give an oil. This oil was dissolved in acetonitrile (100 ml) and then refluxed with isopropylamine (20 ml, 0.23 mol) for 4 hours. The resulting mixture was evaporated in vacuo to give the desired free amine base as an oil. This oil was dissolved in acetone, and an equivalent amount of oxalic acid was dissolved in acetone and added. The resulting acetone solution was concentrated and then concentrated with ethyl ether (100 ml) and 1M.
Partitioned between aqueous KOH (50 ml). The ether layer was separated and extracted with 1M HCl (50 ml). The obtained acidic solution was neutralized with a 1 M KOH aqueous solution and extracted with ethyl ether. The ether layer was separated, dried over anhydrous MgSO _4, filtered and evaporated. The residue was dissolved in acetone and an equivalent amount of oxalic acid was dissolved in acetone and added. The oxalate salt of carbamoylmethyl-4- (2-hydroxy-3-isopropylamino) propoxyphenylacetate which had precipitated after cooling was filtered off and dried. Its melting point was 93-95 ° C. The structural formula of the corresponding free base is:

The results of NMR and elemental analysis were consistent with the above structural formula.

Reference Example 1 In the general esterification method described in Section 1 of Example 3, using the starting materials shown below, the products shown below are also obtained.

General method described in Section 2 of Reference Example 2 Example 3 [i.e., the general formula: After the _{ROOC-C n H 2n -Ar-} OH compound represented by is reacted with an epihalohydrin, such as epichlorohydrin, In the method of reacting the obtained intermediate with a suitable primary amine], if the product of Reference Example 1 is used as a starting material in an equivalent amount instead, the following compound is obtained after an appropriate isolation treatment. .

Reference Example 3 The sulfur-containing compounds listed below are treated with 1 equivalent of m-chloroperbenzoic acid to give the corresponding sulfinyl derivatives, and this thio compound is treated with 2 equivalents of m-chloroperbenzoic acid. Yields the corresponding sulfonyl derivative.

Example 10 By the method according to Examples 7 and 8, the following products were obtained.

R melting point (℃) 141-143 143-146 87-90 Although the present invention has been described with respect to various preferred embodiments,
Various changes, substitutions, without departing from the spirit of the present invention,
Those skilled in the art will understand that omissions and additions can be made. Therefore, the scope of the invention is limited only by the following claims.

Claims (16)

[Claims] 1. A β-adrenergic blocker derivative represented by the following general formula and a pharmaceutically acceptable acid addition salt thereof: In the above formulas, n is an an integer from 0 to (including 0 and 10), R is, C ₆ -C ₁₈ polycycloalkyl -C _p H _2p - group (provided that
p is 0, 1, 2 or _{3); - CH 2 -X-} R 2 group (wherein,
X represents S, SO or SO ₂ , and R ₂ represents a C _{1 to} C ₇ alkyl group); (However, R ₅ represents hydrogen or a C _{1 to} C ₇ alkyl group,
R ₆ represents a C ₁ -C ₇ alkyl group); or (However, R ₅ has the same meaning as described above, R ₇ and R ₈ may be the same or different and each represents hydrogen or a C ₁ -C ₇ alkyl group); R ₁ is C ₁ -C ₇ alkyl Means a group; and Ar is an unsubstituted phenylene group or C ₁ -C ₇ alkyl, C _1-
C ₇ alkyl -O-C ₁ ~C ₇ alkylene -, C ₂ ~C ₈ alkenyl, C ₁ ~ ₇ alkyl -S-, C ₂ ~C ₈ alkenyl -O-,
C ₃ -C ₁₂ cycloalkyl, C ₁ -C ₇ alkyl -CONH-, C ₁
-C ₇ alkyl -CO-, or H ₂ NCO-C ₁ ~C ₇ alkylene - is a phenylene group substituted by group. 2. A C ₆ -C ₁₈ polycycloalkyl-C _p H _2p -group (provided that 0, 1 or 0 is a saturated alicyclic hydrocarbon system in which R has 2 or 3 rings bridged together. The derivative according to claim 1, which has two methyl substituents, the total number of carbon atoms in the polycycloalkyl moiety is 6 to 18, and p is 0, 1 or 2. Acid addition salt. 3. R is adamantyl, bornyl, norbornyl, adamantylmethyl, adamantylethyl, norbornylmethyl or norbornylethyl, preferably R is (adamanto-1-yl) ethyl, (adamanto-1). -Yl) methyl or (norborn-2
-Yl) methyl, the derivative according to claim 2 and an acid addition salt thereof. 4. R is (Wherein R ₅ , R ₆ , R ₇ and R ₈ have the same meanings as defined in claim 1) and the derivative and the acid addition salt thereof according to claim 1. 5. The derivative and the acid addition salt thereof according to claim 4, wherein R ₅ is hydrogen and R ₆ is a C ₁ -C ₇ alkyl group. 6. The derivative and the acid addition salt thereof according to claim 4, wherein R is pivalyloxymethyl or carbamoylmethyl. 7. The derivative and the acid addition salt thereof according to claim 1, wherein n is 0, 1 or 2. 8. The derivative and the acid addition salt thereof according to claim 1, wherein Ar is an unsubstituted phenylene group. 9. The derivative and the acid addition salt thereof according to claim 8, wherein Ar is a 1,4-phenylene group or a 1,3-phenylene group. 10. Ar is CH ₃ CH ₂ —, CH ₃ —, CH ₃ OCH ₂ CH ₂ —, C
_{H 2 = CH-CH 2 -} , CH 3 -S-, CH 2 = CH-CH 2 -O-, CH ₃ CH ₂ CH ₂ CONH−, CH ₃ CONH−, CH ₃ CO− or H ₂ NCO−
A phenylene group having a CH ₂ — group, Claim 1
And the acid addition salt thereof. 11. The group has a structure in which one hydrogen atom on the corresponding ring of the known β-blocker is replaced, and the structure of the compound of general formula (I) is otherwise identical to the structure of the known β-blocker. Yes,
The derivative according to claim 1, wherein the known β-blocker is metoprolol, alprenolol, tiprenolol, oxyprenolol, penbutolol, acebutolol, atenolol or plactrol, and the acid addition salt thereof. 12. The method according to claim 12, The group has a structure in which a functionally non-essential substituent on the corresponding ring of the known β-blocker is substituted, the structure of the compounds of general formula (I) is otherwise identical to that of the known β-blocker. Identical and said known β-blocker is metoprolol, acebutolol, atenolol or plactrol, and each said functionally non-essential substituent is CH ₃ OCH
₂ CH ₂ -group, CH ₃ CH ₂ CH ₂ CONH-group, H ₂ NCOCH ₂ -group or CH ₃
The derivative according to claim 1, which is a CONH-group, and an acid addition salt thereof. 13. The derivative and the acid addition salt thereof according to claim 1, wherein R ₁ is an isopropyl or tert-butyl group. 14. (Adamant-1-yl) ethyl.4-
(2-Hydroxy-3-isopropylamino) propoxyphenylacetate, (adamanto-1-yl) methyl 4- (2-hydroxy-3-isopropylamino)
Propoxyphenyl acetate or (norborn-2
-Yl) methyl-4- (2-hydroxy-3-isopropylamino) propoxyphenylacetate, or a pharmaceutically acceptable acid addition salt of any of these compounds. Derivatives and acid addition salts thereof. 15. Pavilyloxymethyl 4- (2-hydroxy-3-isopropylamino) propoxyphenylacetate or carbamoylmethyl-4- (2-hydroxy-3-isopropylamino) propoxyphenylacetate, or a compound thereof. The derivative according to claim 1, which is a pharmaceutically acceptable acid addition salt, and an acid addition salt thereof. 16. An oxalate salt according to claim 1.
Item 16. The acid addition salt according to any one of items 15.